Increased free androgen index is associated with hypertension in premenopausal women

doi:10.4236/ojog.2011.14045

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Open Journal of Obstetrics and Gynecology, 2011, 1, 228-233

doi:10.4236/ojog.2011.14045 Published Online December 2011 (http://www.SciRP.org/journal/ojog/

OJOG

Published Online December 2011 in SciRes. http://www.scirp.org/journal/OJOG

Increased free androgen index is associated with hypertension

in premenopausal women

Liselott Andersson1, Mats Eliasson2,3, Inger Sundström Poromaa4

1Department of Obstetrics and Gynecology, Sunderby Hospital, Luleå, Sweden;

2Department of Internal Medicine, Sunderby Hospital, Luleå, Sweden;

3Department of Public Health and Clinical Medicine, Umeå University, Luleå, Sweden;

4Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.

Email: [email protected]

Received 15 August 2011; revised 20 September 2011; accepted 4 October 2011.

ABSTRACT

Objective: Increased testosterone and decreased sex

hormone-binding globulin (SHBG) are associated

with a number of adverse cardiovascular risk factors

in postmenopausal women. The aim of this popula-

tion-based study of women aged 25 to 50 was to as-

sess the relationship between free androgen index

(FAI) and cardiovascular risk factors in premeno-

pausal women. Methods: A population-based survey

of 396 premenopausal women with no hormonal trea-

tment was undertaken as part of the Northern Swe-

den MONICA study. The study involved question-

naires, anthropometry and assays of testoste rone and

SHBG. Results: Increased FAI was associated with a

number of cardiovascular risk factors in premeno-

pausal women but this relationship was strongly af-

fected by body mass index (BMI). After adjustment

for age and BMI, FAI was significantly associated

with increased systolic and diastolic blood pressures.

Conclusion: Hyperandrogenism is associated with

increased blood pressure and these findings empha-

size the need to assess cardiovascular risk factors in

women with hyperandrogenism of all ages.

Keywords: Free Androgen Index; Blood Pressure

1. INTRODUCTION

Testosterone is carried in peripheral blood bound to sex

hormone binding globulin, with approximately 1% - 2%

of testosterone free and the remaining testosterone loo-

sely bound to albumin [1]. The free androgen index (FAI),

i.e. the ratio between testosterone and sex hormone bin-

ding globulin (SHBG), may be used as an approximation

of biologically available androgens in women, and lon-

gitudinal studies in aging women indicate that SHBG

levels decrease with increasing age, thus resulting in su-

ccessively increasing amounts of biologically available

androgen in healthy women [2].

Increased testosterone and decreased sex hormone-

binding globulin (SHBG) have been strongly associated

with a number of adverse cardiovascular disease (CVD)

risk factors in postmenopausal women, such as central

adiposity, decreased high-density lipoprotein (HDL)

cholesterol levels and increased systolic and diastolic

blood pressures [3-6]. A nested case-control study of po-

stmenopausal women also suggested that higher free

androgen index was associated with CVD events such as

first occurrence of nonfatal myocardial infarction, coro-

nary revascularization, nonfatal stroke, coronary disease,

or stroke death, although this association was not inde-

pendent of body mass index and other cardiovascular

risk factors [7]. Besides a possible role of androgen hor-

mones and SHBG in cardiovascular disease, low levels

of SHBG have consistently been linked to higher rates of

diabetes [8-9] and might contribute to a more adverse car-

diovascular risk profile in women with diabetes [10-11].

Sex hormone levels may also be associated with CVD

risk factors in pre- and perimenopausal women, although

fewer studies have been conducted in this age-group

[12-14]. In younger women most interest has instead

been devoted to patients with polycystic ovary syndrome

(PCOS), which is a hyperandrogenic population with nu-

merous risk factors for later development of CVD [15].

However, in contrast to healthy women, we have previ-

ously shown that testosterone levels gradually decrease

with increasing age in PCOS women [16], although le-

vels remain elevated in comparison with age-matched

controls [17].

Outside the PCOS patient population, no population-

based studies have been conducted in premenopausal

women concerning the association between free andro-

gen index and cardiovascular risk factors. Thus, the pur-

pose of this population-based study of premenopausal

L. Andersson et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 228-233 229

women aged 25 to 50 was to assess whether free andro-

gen index is associated with risk factors for cardiovas-

cular disease, even in younger women.

2. MATERIALS AND METHODS

2.1. Patients

This study used data from the Northern Sweden compo-

nent of the WHO MONICA study, originally designed to

evaluate risk factors for cardiovascular disease and type

2 diabetes. Briefly, information was collected during a

population-based survey during January to April 2004

[18]. Subjects were randomly selected from population

registers, stratified for age (25 years - 74 years) and gen-

der, in the two most northern counties of Sweden (target

population 312,000). For the entire MONICA study

1250 men and 1250 women were invited, but for the

purpose of this study, only women below age 50 years

were considered. Details of sampling and selection ap-

pear elsewhere and participation rate was 78% [18]. A

total of 500 women 50 years or younger were eligible for

this study. Exclusion criteria were postmenopausal

status (more than 12 months since last menses), ongoing

pregnancy, and use of hormone replacement therapy or

combined oral contraceptives during the last year.

The Research Ethics Committee of Umeå University

and the National Computer Data Inspection Board ap-

proved the Northern Sweden MONICA study. A specific

approval for this sub-study was also obtained from The

Research Ethics Committee of Umeå University. Parti-

cipants gave written consent.

2.2. Study Procedures

Subjects were weighed on an electronic scale. The sub-

jects wore light clothes and no shoes and weight was

measured to the nearest 0.2 kg. Height without shoes

was measured to the nearest centimeter. Body mass in-

dex (BMI) was calculated as weight (kg) divided by

height (m2). To record waist circumference, measure-

ment was performed midway between the lower rib mar-

gin and iliac crest to the nearest 0.0 cm or 0.5 cm. The

blood pressure was measured twice in every person after

a five-minute rest in a sitting position with Hawksley’s

random zero sphygmomanometer. The mean value of the

two measurements was used.

Blood samples were drawn after at least a 4-h fast (in

approximately 65% of subjects blood samples were dra-

wn after an overnight fast).

The participants were asked to complete question-

naires including items about smoking habits, sociodemo-

graphic data and previously known cardiovascular dis-

ease. The questionnaire also included a number of ques-

tions for assessment of reproductive status including

menstrual pattern, last menstrual period, use of oral con-

traceptives and hormone replacement therapy during the

past year.

The highest attained educational level was classified

as primary school (up to 9 years of school), secondary

school (10 years - 12 years of school) and university stu-

dies. Regular smokers smoked at least one cigarette a

day; all other subjects were considered as nonsmokers.

Participants were classified as physically active if re-

porting physical activity more than two hours per week;

all other subjects were considered not physically active.

A positive family history of diabetes, stroke and cardio-

vascular disease was only reported when occurring in

first-degree relatives. A history of gestational diabetes

was only assessed in parous subjects. Hypertension and

elevated serum cholesterol were considered prevalent in

women on medication for these reasons.

2.3. Assays

Total cholesterol was determined by a dry chemistry

method (Vitros 950; Kodak Echtachem, Rochester, NY,

USA). The measurement of total cholesterol is accredi-

ted by the national accreditation body, SWEDAC, with

coefficients of variation of 3.6% at 3.91 mmol·L–1 and

3.1% at 6.66 mmol·L–1.

An oral glucose tolerance test (OGTT; 75 g glucose)

was performed in a random sub-sample (approximately

65%) of the non-diabetic participants after an overnight

fast. A venous blood sample was taken immediately be-

fore the glucose load and after two hours. Glucose levels

were analyzed without delay on a HemoCue Glucose

201 device (HemoCue AB, Angelholm, Sweden) and

converted to plasma glucose levels by a correction factor

of 1.11. According to previous validation of this proce-

dure, the adjusted data for glucose showed a high corre-

lation to plasma glucose simultaneously measured by the

hexokinase method in a sub-sample [18]. SHBG and

testosterone were analyzed on a Modular E170 (Roche

Diagnostics, Mannheim, Germany). The total coefficients

of variation of the instrument for the analytes were 1.5%

at 43 nmol/L for SHBG and 6.8% at 3.9 nmol/L for tes-

tosterone. Free androgen index was calculated as testos-

terone (nmol/L)/SHBG (nmol/L) × 100.

Physical and biochemical parameters were analyzed

using partial correlation test with adjustment for age and

BMI and with logarithmic FAI. The women were grou-

ped into quartiles depending on level of FAI. Dichoto-

mized and continuous variables were compared between

groups using linear or logistic regression analysis and

adjusted for age and BMI. The software package SPSS

(version 12.0) was used for statistical analyses.

3. RESULTS

Fifteen postmenopausal women, 53 women on combined

oral contraceptives, 16 women on hormone replacement

L. Andersson et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 228-233

230

OJOG

therapy, 10 pregnant women and 20 women lacking a blood

sample were excluded. Hence, 396 women 50 years or

younger were included in the study.

Sociodemographic, anthropometric and reproductive

data are presented in Table 1 and given according to

quartiles of FAI. Women in the highest quartile, i.e. with

the highest level of free testosterone (or the lowest level

of SHBG), were significantly older and had higher BMI

than those in the lower three quartiles. BMI was 4.5

kg/m2 higher in the fourth FAI quartile compared to the

lowest. Compared to the lowest FAI quartile, women

with the highest FAI had lower educational level and

were more often smokers. Otherwise, women in the dif-

ferent FAI quartiles did not differ regarding use of snuff

or physical activity.

Hypertension was significantly more common among

women in the highest FAI quartile (Table 2). In the low-

est FAI quartile was hypertension prevalent in 19.2% of

the subjects while 35.4% of women in the highest quar-

tile had hypertension.

Table 1. Physical characteristics, sociodemographic and reproductive data in women according to free androgen index quartiles.

FAI lowest

0.13 - 1.10 (n = 99)

FAI

1.11 - 1.84 (n = 99)

FAI

1.85 - 3.07 (n = 99)

FAI highest

3.08 - 68.9 (n = 99)

Age (years ± SD) 39.3 ± 7.2 38.5 ± 6.7 37.3 ± 7.3 41.0 ± 5.5a

Parity (mean ± SD) 2.2 ± 1.0 2.4 ± 1.2 2.0 ± 0.9 2.4 ± 0.8

BMI 24.2 ± 3.6 24.6 ± 4.6 26.1 ± 4.6c 28.4 ± 6.2b

Waist, cm 80.2 ± 10.0 80.3 ± 11.3 84.7 ± 12.6 90.9 ± 14.3a

Marital status Living single OR (95% CI) 1 1.40 (0.72 - 2.72) 0.70 (0.33 - 1.46) 0.88 (0.42 - 1.85)

Cases, n 20 (20.2%) 24 (24.5 %) 13 (13.1%) 18 (18.2%)

Educational level < university level OR (95% CI) 1 1.10 (0.62 - 1.93) 0.87 (0.49 - 1.53) 1.98 (1.05 - 3.75)d

Cases, n 59 (59.6%) 63 (63.6%) 57 (57.6%) 73 (74.5%)

Smoking Smokers OR (95% CI) 1 1.62 (0.77 - 3.41) 3.50 (1.74 - 7.04) d 2.38 (1.13 - 5.02) d

Cases, n 13 (13.1%) 21 (21.4%) 35 (35.4%) 26 (26.5%)

Snuff Snuff users OR (95% CI) 1 1.43 (0.62 - 3.31) 1.66 (0.72 - 3.83) 1.51 (0.62 - 3.70)

Cases, n 10 (10.2%) 16 (16.3%) 14 (14.3%) 14 (14.1%)

Physically Not active OR (95% CI) 1 0.63 (0.29 - 1.38) 1.20 (0.59 - 2.43) 1.04 (0.50 - 2.18)

active Cases, n 18 (18.2%) 12 (12.1%) 23 (23.2%) 23 (23.2%)

ap < 0.05 - 0.01 compared to the two intermediate FAI quartiles, one-way ANOVA with post hoc Tukey Honestly Significance test. bp < 0.05 - 0.001 compared

to all other FAI quartiles, one-way ANOVA with post hoc Tukey Honestly Significance test. cp < 0.05 compared to the lowest FAI quartile, one-way ANOVA

with post hoc Tukey Honestly Significance test. dp < 0.05 - 0.01 compared to the lowest FAI quartile, multivariate logistic regression adjusted for age and body

mass index.

Table 2. Data on diabetes, cardiovascular disease and family history in women according to free androgen index quartiles.

FAI lowest

0.13 - 1.10 (n = 99)

FAI

1.11 - 1.84 (n = 99)

FAI

1.85 - 3.07 (n = 99)

FAI highest

3.08 - 68.9 (n = 99)

Diabetes OR (95 % CI) 1 1.12 (0.07 - 18.70) n.c. 4.62 (0.49 - 43.22)

cases, n (%) 1 (1.0%) 1 (1.0%) 0 5 (5.1%)

Hypertension OR (95 % CI) 1 0.55 (0.24 - 1.22) 0.98 (0.47 - 2.03) 2.00 (1.01 - 4.00) a

cases, n (%) 19 (19.2%) 11 (11.1%) 19 (19.2%) 35 (35.4%)

Elevated serum cholesterol OR (95 % CI) 1 1.50 (0.40 - 5.66) 1.26 (0.32 - 5.00) 2.14 (0.63 - 7.28)

cases, n (%) 4 (4.0%) 6 (6.1%) 5 (5.1%) 12 (12.1%)

Previous gestational diabetes OR (95 % CI) 1 1.65 (0.57 - 4.74) 0.68 (0.20 - 2.35) 2.30 (0.81 - 6.56)

cases, n (%) 6 (6.1%) 10 (10.1%) 5 (5.1%) 15 (15.2%)

Family history of diabetes OR (95 % CI) 1 1.12 (0.58 - 2.40) 1.00 (0.46 - 2.21) 1.86 (0.90 - 3.83)

cases, n (%) 16 (16.2%) 17 (17.2%) 15 (15.2%) 29 (29.3%)

Family history of hypertension OR (95 % CI) 1 1.04 (0.58 - 1.86) 1.55 (0.85 - 2.81) 1.11 (0.61 - 2.04)

cases, n (%) 48 (48.5%) 47 (47.5%) 55 (55.6%) 56 (56.6%)

Family history of myocardial OR (95 % CI) 1 0.68 (0.23 - 2.01) 1.00 (0.36 - 2.76) 0.51 (0.16 - 1.64)

infarction cases, n (%) 9 (9.1%) 6 (6.1%) 8 (8.1%) 5 (5.1%)

Family history of stroke OR (95 % CI) 1 0.84 (0.25 - 2.89) 0.16 (0.02 - 1.42) 0.41 (0.09 - 1.80)

cases, n (%) 6 (6.1%) 5 (5.1%) 1 (1.0%) 3 (3.0%)

ap < 0.01 compared to all other FAI quartiles, multivariate logistic regression adjusted for age and body mass index.

L. Andersson et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 228-233 231

Among women within the highest FAI quartile cho-

lesterol, waist circumference, and blood pressure were

significantly higher than in the three groups with lower

FAI. However, after adjustment for age and BMI, only

systolic and diastolic blood pressures were significantly

higher (Table 3). Blood pressure was 9/7 mm Hg higher

in the highest FAI quartiles than in the lowest quartile.

Similarly, free androgen index was significantly and

positively correlated with systolic and diastolic blood

pressures (Table 4).

4. DISCUSSION

The main finding of the present study was that young

and premenopausal women within the highest quartile of

free androgen levels had several risk factors for cardio-

vascular disease. However, when adjusted for age and

BMI the only associations that remained were the ones

between high FAI and high systolic and diastolic blood

pressures, respectively. This finding is in line with pre-

vious studies in pre- and perimenopausal [14,19] as well

as postmenopausal women [3-6]. In perimenopausal wo-

men free androgen index was positively and independ-

ently associated with a number of cardiovascular risk

factors such as total cholesterol, low-density lipoprotein

cholesterol, lipoprotein (a), insulin, plasminogen activator

Table 3. Physical and biochemical measures in women ac-

cording to free androgen index quartiles.

FAI lowest

0.13 - 1.10

(n = 99)

FAI

1.11 - 1.84

(n = 99)

FAI

1.85 - 3.07

(n = 99)

FAI highest

3.08 - 68.9

(n = 99)

Fasting glucose,

mmol/l 5.1 ± 0.5 5.2 ± 0.5 5.1 ± 0.6 5.5 ± 1.6

2-hour glucose,

OGTT, mmol/l 5.3 ± 1.3 5.5 ±1 .0 5.5 ± 1.6 5.9 ± 2.2

Total chole-sterol,

mmol/l 5.1 ± 1.1 4.9 ± 0.9 5.2 ± 1.0 5.5 ± 1.1

SBP, mmHg 115 ± 15 112 ± 11 114 ± 11 124 ± 19 a

DBP, mmHg 72 ± 9 71 ± 8 71 ± 8 79 ± 13b

ap < 0.01, bp < 0.001 compared to all other FAI quartiles, ANCOVA ad-

justed for age and body mass index. For the glucose variable and for the 2

hour glucose variable, data was missing in 161 (40.7%) women and in 212

(53.5%) women, respectively. For all other variables, data was missing in

0.3% - 1.0% of women. OGTT, oral glucose tolerance test, SBP systolic

blood pressure, DBP diastolic blood pressure.

Ta b l e 4 . Partial correlations between free androgen index and

physical or biochemical parameters, adjusted for age and body

mass index.

Fasting

glucose

2 hour

glucose Cholesterol WC SBPDBP

Free androgen

index –0.018 0.119 0.052 –0.08 0.213a0.262b

ap < 0.01, bp < 0.001. For the glucose variable, data was missing in 161

(40.7%) women. For all other variables, data was missing in 0.3% - 1.0% of

women. SBP systolic blood pressure, DBP diastolic blood pressure, WC

waist circumference.

inhibitor-1, tissue plasminogen activator and high sensi-

tive c-reactive protein, systolic and diastolic blood pres-

sures [14].

In our cohort of women across different age groups,

women with the highest free androgen index were found

to be significantly older than the remaining women. This

finding is in line with previous longitudinal studies indi-

cating that increased BMI over time is closely related to

lowering of SHBG levels [20]. However, a recent longi-

tudinal study in healthy women suggested that, not only

did SHBG levels decline with increasing age, testoster-

one levels also displayed a gradual increase from the age

of 40 and onwards [2].

We were also able to confirm prior findings of an as-

sociation between free androgen levels and increased

systolic and diastolic blood pressures, although the ma-

jority of these studies were conducted in older, postme-

nopausal women [3-6,12-14,19]. In addition, the preva-

lence of manifest hypertension was approximately 35%

among women with the highest FAI. Notably, in our pre-

vious longitudinal study of 40-year old PCOS women,

systolic and diastolic did not differ from controls fol-

lowing adjustment for BMI, and manifest hypertension

was only prevalent in approximately 16% of PCOS wo-

men [21].

The free androgen index is mainly driven by the SHBG

levels and the best known function of SHBG is to regu-

late the availability of biologically active free testoster-

one and estradiol and their metabolic clearance rate [22].

SHBG production is stimulated by estradiol and inhib-

ited by androgens indicating that a high level of SHBG

would temper the unfavorable effects of free androgens

on blood pressure. Besides its contribution to free an-

drogen levels, low levels of SHBG have consistently

been linked to insulin resistance [23], higher rates of

diabetes [8-9,23] and might contribute to a more adverse

cardiovascular risk profile in women with diabetes

[10-11]. Testosterone on its own may also contribute to

the increased blood pressure found in our women within

the highest FAI quartile. Previous animal studies have

indicated a prohypertensive effect of androgens which

may be mediated through increased vascular tone via

upregulation of thromboxane A2 expression, norepine-

phrine, angiotensin II and endothelin-1 synthesis [24].

Other means by which androgens may influence blood

pressure also include effects on the renin-angiotensin-al-

dosterone system [24].

Our findings also indicate a clear association between

obesity and increased waist circumference, as a measure

of central adiposity, and elevated free androgen levels.

This finding is in line with a number of studies [3-6,

12-14,19,25] and is further evidenced by studies sug-

gesting that weight loss, whether induced by bariatric su-

rgery, anti-obesity agents, or life-style interventions, will

L. Andersson et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 228-233

232

reduce androgen levels [25-26].

The major limitation of this study is the relatively

small sample size, which might raise questions whether

this study was adequately powered for some of the ana-

lyses. However, the study has pointed out that increased

FAI is associated with a number of cardiovascular risk

factors but these relationships seem to be strongly af-

fected by BMI. Free androgen index was significantly

and independently associated with increased systolic and

diastolic blood pressures, emphasizing the need to assess

cardiovascular risk factors in women with hyperandro-

genism across all ages.

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